Silylated indanyloxyacetates

ABSTRACT

Indanyloxy compounds having 2-alkynyl substituents which exhibit diuretic, saluretic, and uricosuric activity are described. The compounds are obtained according to a process involving selective etherification of a 5-hydroxyindanone followed by alkynylation with a silylated alkynyl bromide to provide novel silylated intermediates which are hydrolyzed to indanyloxy compounds such as (6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of application Ser. No. 027,961 filed Apr. 9, 1979,now U.S. Pat. No. 4,247,715.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel indanyloxyacetic acid derivatives morespecifically described as 1-oxo-2-(optionallysubstituted)phenyl-2-alkynyl-5-indanyloxyacetic acids. These compoundshave drug and bio-affecting properties and, in particular, are diureticand uricosuric agents with relatively low toxicity. The invention isalso concerned with a method for preparing the indanyloxyacetic acidcompounds and novel silylated intermediates therefor.

2. Description of the Prior Art

Cragoe, Jr., et al., U.S. Pat. No. 4,096,267 concerns(1-oxo-2-aryl-2-substituted-5-indanyloxy)alkanoic acids having diuretic,saluretic, and uricosuric activity. The following specific compounds ofFormula (1) illustrate alkyl- and alkenyl-2-substituents.

    ______________________________________                                         ##STR1##                 Formula (1)                                                            R                                                          ______________________________________                                        (1a)                 methyl                                                   (1b)                 allyl                                                    ______________________________________                                         *Ph = phenyl                                                             

According to the '267 patent, such compounds are prepared by variousprocesses including an etherification step illustrated by the flowdiagram below of the procedure of Example 1 (Step E). ##STR2##(1-Oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (3) is obtainedaccording to the above flow diagram in a relatively low yield of about6% with recovery of starting material even though an extended reactionperiod of some 48 hours was employed.

deSolms, et al., J. Med. Chem., 21, 437-443 (1978) discussesstructure-activity relationships of the(2-alkyl-2-aryl-1-oxo-5-indanyloxy)acetic acids of U.S. Pat. No.4,096,267. The article identifies the preferred compound of the seriesas (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid(MK-196). Using this compound as a standard for comparison, the authorsconcluded that as the "2-alkyl substituent" increases in size frommethyl to ethyl, etc., activity drops considerably.

Cragoe, Jr., et al., U.S. Pat. No. 3,984,465 is concerned with(1-oxo-2-alkyl-2-substituted-5-indanyloxy)acetic acids having diuretic,saluretic, and uricosuric activity. Generically disclosedindanyloxyacetic acids include compounds wherein 2-substituents arealkyl, alkenyl, or alkynyl. The following compounds of formula (4)illustrating alkyl- and alkenyl-2-substituents are specificallydisclosed in the '465 patent. However, the patent does not describe orset forth in any manner a specific example of a "2-alkynyl" substitutedindanyloxyacetic acid.

    ______________________________________                                         ##STR3##                 Formula (4)                                                            R                                                          ______________________________________                                        (4a)                 methyl                                                   (4b)                 ethyl                                                    (4c)                 allyl                                                    ______________________________________                                    

Cragoe, Jr., U.S. Pat. No. 4,070,539 concerns 2-alkyl derivatives of1-oxo-5-indanyloxyalkanoic acid which are said to be diuretic andsaluretic. Some of the compounds are reportedly also capable ofmaintaining or reducing uric acid levels.

Waltersdorf, Jr. et al., J. Med. Chem. 20, 1400-1408 (1977) discussesdiuretic structure-activity relationships of certain(1-oxo-5-indanyloxy)acetic acids having a mono-alkyl substituent in the2-position or bearing an additional "2-substituent" such as alkyl orallyl. The compounds studied were prepared according to processesdescribed in Cragoe, et al., U.S. Pat. Nos. 3,984,465 and 4,070,539.

The instant invention provides a process for preparing indanyloxycompounds of Formula I (infra) involving selective etherification of a2-(phenyl)-substituted-5-hydroxyindanone with ethyl bromoacetate to thecorresponding indanyloxyacetate and subsequent alkynylation of the"2-position" with a "protected" alkynyl halide such astrimethylsilylpropargyl bromide followed by hydrolysis of the alkynylintermediates. This process constitutes a decided improvement overanalogous prior art procedures of Cragoe, et al., U.S. Pat. Nos.4,070,539 and 4,096,267, in that substantially improved yields areobtained.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION

Broadly described, this invention is concerned with novel indanyloxycompounds, and to a process and silylated intermediates for preparationthereof. The instant indanyloxy compounds possess diuretic anduricosuric properties which are valuable in treating conditionsassociated with electrolyte and fluid retention, particularly in thetreatment of hypertension. The indanyloxy compounds of the instantinvention are characterized by Formula I ##STR4## wherein X is halo;

R₁ is phenyl or p-halophenyl;

R₂ is propargyl or 3-butynyl; and a non-toxic pharmaceuticallyacceptable salt thereof.

It is to be understood that the term "halo" as used herein refers tobromine, iodine, and fluorine, and most preferably chlorine.

The term "non-toxic pharmaceutically acceptable salt" used herein refersto a combination of a Formula I compound with a relatively non-toxicbase, the cation of which is relatively pharmaceutically ineffective inthe usual dosage. Acceptable salts of the substances of Formula Iinclude those of alkali metals, alkali earth metals and amines such asammonia, primary and secondary amines, and quarternary ammoniumhydroxides. Particularly preferred metal cations are those derived fromalkali metals such as sodium, potassium, lithium, and the like; alkalineearth metals such as calcium, magnesium, and the like; and other metalssuch as aluminum, iron and zinc and other related metals. Preparation ofthe salts may be carried out in conventional manner by treating asolution or suspension of the acid with alkali metal and alkaline earthmetal hydroxides, carbonates, bicarbonates, amines, or quarternaryammonium hydroxides to form the corresponding alkali metal, alkalineearth metal, amine or quaternary ammonium salts. Conventionalconcentration or crystallization techniques are employed in isolatingthe salts. Examples of primary, secondary or tertiary amines, orquaternary ammonium hydroxides providing pharmaceutically acceptablesalts are: methylamine, dimethylamine, trimethylamine, ethylamine,N-methylhexylamine, benzylamine, alpha-phenylethylamine,ethylenediamine, piperidine, 1-methylpiperazine, morpholine,pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine,triethanolamine, tetramethyl ammonium hydroxide, tetraethyl ammoniumhydroxide, benzyltrimethyl ammonium, and the like.

The indanyloxy compounds characterized by Formula I are obtained by aseries of reactions involving etherification of an appropriate5-hydroxyindanone followed by alkynylation with a silylated alkynylbromide to silylated intermediates which are hydrolyzed to theindanyloxy compounds of the invention as set forth in the followingprocess steps which comprise

(a) etherifying a 5-hydroxyindanone of Formula II ##STR5## wherein R₁ isphenyl or p-halophenyl and X is halo with BrCH₂ CO₂ R₃ in which R₃ islower alkyl of 1 to 4 carbon atoms inclusive in the presence of analkali metal alkoxide in an alkanol solvent to provide anindanyloxyacetate of Formula III ##STR6## wherein X, R₁ and R₃ are asdefined above;

(b) alkynylating the formula III compound with (CH₃)₃SiC.tbd.C--(CH₂)_(n) --Br in which n is 1 or 2 in the presence of acarbonate base such as potassium or sodium carbonate in a reaction inertsolvent such as dimethylformamide to provide atrimethylsilylalkynylindanyloxyacetic acid of Formula IV ##STR7##wherein X, n, R₁ and R₃ are as defined above;

(c) treating the formula IV compound with a concentrated solution (about40-60%) of an alkali metal base such as sodium or potassium hydroxide inethanol to provide the Formula I compound.

In the etherifying reaction (a) of the above process, selection of baseand solvent is of particular importance with respect to preventing sidereactions and maximizing yields of indanyloxyacetates of Formula III.Preferably, the reaction is carried out with an alkali metal alkoxidesuch as sodium or potassium alkoxide in an alkanol solvent such asmethanol or ethanol. Bases such as sodium or potassium carbonate andsolvents such as dimethylformamide or acetone are not suitable in thatthe reaction does not go to completion or substantial alkylation at the2-position of the indanone starting material in addition to alkylationof the desired "5-OH" moiety results. For instance, reaction of2-phenyl-5-hydroxy-6,7-dichloroindanone (IIa, R₁ =phenyl, X=chloro) withethyl bromoacetate in the presence of sodium ethoxide and ethanolprovides indanyloxyacetate IIIa (R₁ =phenyl, R₃ =ethyl, X=chloro) in a77% yield whereas reaction with ethyl bromoacetate in the presence ofpotassium carbonate employing dimethylformamide as solvent providedmixtures of IIIa and appreciable amounts of undesired 2-alkylatedmaterial of formula V. ##STR8## Table I below sets forth results ofetherification attempts employing indanone IIa with various alkylatingagents, bases and solvents.

                  TABLE 1                                                         ______________________________________                                        Etherification of 2-Phenyl-5-hydroxy-6,7-dichloroindanone (IIa)               Alkylating                  Temperature/                                                                           Identified                               Agent     Base     Solvent  Time     Material                                 ______________________________________                                        ClCH.sub.2 CO.sub.2 Me                                                                  K.sub.2 CO.sub.3                                                                       acetone  reflux/4 hrs.                                                                          S.M..sup.a                               BrCH.sub.2 CO.sub.2 Et                                                                  K.sub.2 CO.sub.3                                                                       acetone  reflux/  1:1 mixture                                                          2.5 Hrs. IIIa, V                                  BrCH.sub.2 CO.sub.2 Et                                                                  K.sub.2 CO.sub.3                                                                       DMF      50°/1.5 hrs.                                                                    V and S.M.                               BrCH.sub.2 CO.sub.2 Et                                                                  Cs.sub.2 CO.sub.3                                                                      acetone  reflux/5 hrs.                                                                          1:1 mixture                                                                   IIIa, V                                  BrCH.sub.2 CO.sub.2 Et                                                                  NaOEt    ethanol  reflux/5 hrs.                                                                          IIIa                                     ______________________________________                                         .sup.a starting material.                                                

Step (b) of the above process, wherein an alkynyl radical is attached toposition 2 of the indanyloxyacetate (III), is preferably carried outwith a silylated alkynyl halide such as1-bromo-3-(trimethylsilyl)-2-propyne or1-bromo-4-(trimethylsilyl)-3-butyne. The reaction may be conducted attemperatures ranging from about 25° to 80°, preferably at 55° to 65°, inthe presence of a carbonate base such as potassium carbonate.Dimethylformamide is preferably employed as a reaction solvent but anysolvent which is inert or substantially inert to the reactants and inwhich the reagents are reasonably soluble may be employed. The silylatedintermediates of Formula III are obtained in nearly quantitative yieldaccording to this procedure and can be generally used without furtherpurification in step (c).

Step (c) of the above process (wherein the silylated indanone ester ofFormula (IV) is converted to the corresponding Formula I product by basehydrolysis) is preferably carried out with a relatively concentratedsolution of sodium hydroxide or potassium hydroxide in an alkanolsolvent such as ethanol at 20°-30°. Preferably, from 3-12 (mostpreferably from 5-7) mole equivalents of a 50% solution of the base inethanol is employed per each mole of silylated material. Selection ofthe solvent and base for the hydrolysis of the ester and desilylation iscritical to maximizing yields of the Formula I compounds. For instance,treatment of methyl[1-oxo-2-phenyl-2-(3-trimethylsilylpropargyl)-6,7-dichloroindanyloxy]acetateat room temperature with 10% potassium hydroxide in methanol provides a37% yield of Ia (R₁ =phenyl, R₂ =propargyl, X=chloro), m.p. 235°-241°.However, under these reaction conditions, ether interchange of the5-(carbethoxymethoxy) function is also effected resulting in substantialproduction of the methyl ester of Formula VI, m.p. 161°-163°. ##STR9##When the above hydrolysis and desilylation of step (c) is carried outwith methyl or ethyl esters of[1-oxo-2-phenyl-2-(3-trimethylsilylpropargyl)-6,7-dichloroindanyloxy]aceticacid employing about 6 mole equivalents of 50% aqueous sodium hydroxidein ethanol, the yield of indanyloxy product Ia is substantiallyimproved. For instance, the above mentioned ethyl ester in Step (c)afforded (6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)aceticacid in 80-90% yield. Thus, the process of the instant invention asdescribed in steps (a-c) above provides Formula I compounds from5-hydroxyindanones of Formula II in overall yields of about 60-75%.

A preferred embodiment of the present invention is a process forpreparing an indanyloxy compound characterized by Formula Ia ##STR10##which comprises

(a) etherifying a 5-hydroxyindanone of Formula IIa ##STR11## with ethylbromoacetate in the presence of sodium ethoxide and absolute ethanol toprovide an indanyloxyacetate of Formula IIIa

(b) alkynylating IIIa with 1-bromo-3-(trimethylsilyl)-2-propyne in thepresence of potassium carbonate in dimethylformamide to provide atrimethylsilylalkynylindanyloxyacetic acid of Formula IVa ##STR12## andthereafter;

(c) treating IVa with 50% sodium hydroxide or potassium hydroxide inethanol to provide Ia.

As indicated hereinabove, the Formula I indanyloxy compounds arediuretic, saluretic, and uricosuric agents. When administered to mammalsin conventional vehicles, these compounds effectively reduce the amountof sodium and chloride ions in the body and generally alleviateconditions usually associated with edema or fluid retention by reducingdangerous excesses of fluid levels with corresponding decrease in blooduric acid concentration.

For the purpose of treating excesses of fluid retention and associateddiseases such as hypertension in mammals, the therapeutic process of theinstant invention is carried out by systemically administering to amammal in need of such treatment a diuretic, uricosuric orantihypertensive effective amount of a compound selected from the groupcharacterized by Formula I or pharmaceutically acceptable salts thereof.By systemic administration, it is intended to include both oral andparenteral routes. Examples of parenteral administration areintramuscular, intravenous, intraperitoneal, rectal and subcutaneousadministration. Dosage will vary with the form of administration and theparticular compound chosen. However, from about 0.025 mg. to about 20mg./kg. of body weight of a compound characterized by Formula Iadministered in effective single or multiple dosage units is generallysatisfactory.

Indanyloxy Formula I compounds may be compounded and formulated withorganic or inorganic solid materials or liquids which arepharmaceutically acceptable carriers to provide pharmaceuticalcompositions of unit dosage forms suitable for administration tomammals. The pharmaceutical compositions may take the form of tablets,capsules, powder, granules, suspension, solutions, and the like.Suitable pharmaceutical carriers comprise both solids and liquids suchas corn starch, lactose, calcium phosphate, stearic acid,polyethyleneglycol, water, sesame seed oil, peanut oil, and so forth.Standard formulating procedures are employed to prepare thepharmaceutical compositions as illustrated by the followingrepresentative dosage form:

    ______________________________________                                        Dry-Filled Capsules Containing                                                10 mg. of Active Ingredient Per Capsule                                       Ingredient            Amount                                                  ______________________________________                                        (6,7-Dichloro-1-oxo-2-phenyl-2-                                               propargyl-5-indanyloxy)acetic acid                                                                    10     mg.                                            Lactose                 189    mg.                                            Magnesium stearate      1      mg.                                            Capsule (Size No. 1)    200    mg.                                            ______________________________________                                    

The powdered(6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid,lactose and magnesium stearate are thoroughly admixed and then filledinto No. 1 dry gelatin capsule.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. It isto be understood that the invention is not limited solely to theparticular examples given below. All temperatures expressed herein arein degrees Celsius. Regarding the "NMR" data given below, chemical shiftdelta values are in parts per million with tetramethylsilane as internalreference.

EXAMPLE 1 Preparation of(6,7-Dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic Acid

STEP (a). Sodium (629 mg., 27.3 mmol) is added to 50 ml. of absoluteethanol under a nitrogen atmosphere. After the sodium dissolves,6,7-dichloro-5-hydroxy-2-phenyl-1-indanone (7.35 g., 25.1 mmol), and 75ml. of additional absolute ethanol are added followed by 3.1 ml. ofethyl bromoacetate (28.1 mmol). The mixture is stirred at roomtemperature for 1 to 2 hrs., refluxed for 5-16 hrs. and then poured intoa dilute acid-ether mixture. The crude reaction product collected andcrystallized from 1:1 ethanol-water with activated charcoal provides a70% yield of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate,m.p. 113.5°-115°.

A sample of the indanyloxyacetate prepared according to the aboveprocedure employing a 16 hr. reflux period and purified by ethertrituration of the reaction product rather than crystallization meltedat 113°-115° (77% yield) and had the following elemental analysis.

Anal. Calcd. for C₁₉ H₁₆ Cl₂ O₄ : C, 60.18; H, 4.26; Cl, 18.70. Found:C, 59.99; H, 4.36; Cl, 18.80.

NMR (CDCl₃): 1.31 (3,t, 7.5 Hz), 3.10 (1,dd, 4.2 and 16.2 Hz), 3.53(1,dd, 7.5 and 16.2 Hz), 3.88 (1,dd, 4.2 and 7.5 Hz), 4.26 (2,q, 7.5Hz), 4.80 (2,s), 6.76 (1,s), 7.22 (5,m).

STEP (b). A solution of 1-bromo-3-(trimethylsilyl)-2-propyne (2.87 g.,15.0 mmol) prepared according to methods of Corey, Tet. Lett., 3963(1973) and Miller, Syn. Comun., 2, 267 (1972) in 50 ml. ofdimethylformamide is added to a mixture of ethyl(6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate (2.9 g., 7.65 mmol)and powdered potassium carbonate (2.65 g., 19.2 mmol) under an argonatmosphere. After stirring at 60° for a period of 2 hr. and cooling toroom temperature, ether is added to the reaction mixture followed bydilute hydrochloric acid. The acidified solution is extracted with etherand the ethereal extract sequentially washed with water and brine, andthen dried over magnesium sulfate. Removal of solvent under reducedpressure affords 4.72 g. of tan solid. Crystallization of this materialfrom cyclohexane provides 3.26 g., (87% yield) of ethyl[6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate,m.p. 111.5°- 113° (corr.).

Anal. Calcd. for C₂₅ H₂₆ Cl₂ O₄ Si: C, 61.35; H, 5.36. Found: C, 61.15;H, 5.29.

NMR (CDCl₃): -0.04 (9,s), 1.31 (3,t, 7.5 Hz), 2.94 (2,s), 2.58 (2,m),4.30 (2,q, 7.5 Hz), 4.79 (2,s), 6.80 (1,s), 7.29 (5,m).

STEP (c). A solution of 50% sodium hydroxide (2.5 g.) in 50 ml. of abs.ethanol is added to a suspension of ethyl[6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate(3.08 g., 6.3 mmol) in 100 ml. of abs. ethanol under an argonatmosphere. The mixture stirred at room temperature for a period of 5hr. (excluding light) and mixed with water provides a clear yellowsolution which is first extracted with ether and then acidified withdilute hydrochloric acid. The acidified solution is extracted with 1:1ether-ethyl acetate which, after washing with brine and drying overmagnesium sulfate, is concentrated under reduced pressure to afford 2.22g. (91% yield) of(6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid as atan solid, m.p. 238.5°-241.5° (corr.). Crystallization from isopropanolaffords the indanyloxyacetic acid product as white needles, m.p.237.5°-240° (corr.). This material is solvated with 0.17 mole ofisopropanol, according to NMR analysis, and has the following elementalanalysis.

Anal. Calcd. for C₂₀ H₁₄ Cl₂ O₄.0.17C₃ H₈ O: C, 61.68; H, 3.88; Cl,17.76. Found: C, 61.46; H, 4.13; Cl, 17.55.

NMR (DMSO-d₆): 1.04 (1,d, 6.0 Hz), 2.74 (1,t, 2.0 Hz), 2.96 (2,d, 2.0Hz), 3.55 (2,s), 5.01 (2,s), 7.28 (5,m), 7.38 (1,s), 13.20 (1,bs).

Analytically pure(6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid (m.p.236°-240°) is also obtained by dissolving the isolated reaction productfrom the ether-ethyl acetate extract in dilute sodium hydroxide(employing activated charcoal) and re-precipitating with dilutehydrochloric acid.

Anal. Calcd. for C₂₀ H₁₄ Cl₂ O₄ : C, 61.72; H, 3.63; Cl, 18.22. Found:C, 61.33; H, 3.40; Cl, 18.20.

NMR (DMSO-d₆): 2.74 (1,m), 2.96 (2,m), 3.55 (2,s), 5.01 (2,s), 7.28(5,m), 7.38 (1,s).

EXAMPLE 2 Preparation of Indanyloxyacetates of Formula III

(1) Methyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate. Reactionof 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone with methyl bromoacetateaccording to the procedure of Example 1, STEP (a), affords the titlecompound, m.p. 151.5°-153° (from benzenecyclohexane).

Anal. Calcd. for C₁₈ H₁₄ Cl₂ O₄ : C, 59.20; H, 3.87. Found: C, 59.30; H,3.82.

NMR (CDCl₃): 3.33 (2,m), 3.83 (3,s), 3.90 (1,m), 4.81 (2,s), 6.79 (1,s),7.22 (5,m).

(2) Ethyl [6,7-dichloro-1-oxo-2-(p-chlorophenyl)-5-indanyloxy]acetate.Reaction of 6,7-dichloro-5-hydroxy-2-(p-chlorophenyl)-1-indanone withethyl bromoacetate according to the procedure of Example 1, STEP (a),affords the title compound, m.p. 159.5°-160° (crystallized fromethanol-acetone).

Anal. Calcd. for C₁₉ H₁₅ Cl₃ O₄ : C, 55.17; H, 3.66; Cl, 25.71. Found:C, 55.10; H, 3.60; Cl, 25.76.

NMR (CDCl₃): 1.32 (3,t, 7.2 Hz), 3.08 (1,dd, 4.5 and 17.6 Hz), 3.55(1,dd, 8.2 and 17.6 Hz), 3.88 (1,dd, 4.5 and 8.2 Hz), 4.29 (2,q, 7.2Hz), 4.80 (2,s), 6.78 (1,s), 7.16 (4,m).

(3) Ethyl [6,7-dichloro-1-oxo-2-(p-fluorophenyl)-5-indanyloxy]acetate.Reaction of 6,7-dichloro-5-hydroxy-2-(p-fluorophenyl)-1-indanone withethyl bromoacetate according to the procedure of Example 1, STEP (a),affords the title compound. Crystallization from ethanol providesanalytically pure material, m.p. 143°-144°.

Anal. Calcd. for C₁₉ H₁₅ Cl₂ FO₄ : C, 57.46; H, 3.81; Cl, 17.86. Found:C, 57.46; H, 3.80; Cl, 17.83.

NMR (CDCl₃): 1.31 (3,t, 7.2 Hz), 3.07 (1,dd, 4.0 and 17.4 Hz), 3.55(1,dd, 8.0 and 17.4 Hz), 3.86 (1,dd, 4.0 and 8.0 Hz), 4.28 (2,q, 7.2Hz), 4.80 (2,s), 6.79 (1,s), 7.04 (4,m).

(4) Ethyl [6,7-dibromo-1-oxo-2-phenyl-5-indanyloxy]acetate. Reaction of6,7-dibromo-5-hydroxy-2-phenyl-1-indanone with ethyl bromoacetateaccording to the procedure of Example 1, STEP (a), affords the titlecompound.

EXAMPLE 3 Preparation of Silated Indanone Esters of Formula IV

(a) Methyl[6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.

Reaction of methyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetatewith 1-bromo-3-(trimethylsilyl)-2-propyne according to Example 1, STEP(b), affords the title compound, m.p. 125.5°-127° (fromcyclohexane-methylene chloride) in 74% yield.

Anal. Calcd. for C₂₄ H₂₄ Cl₂ O₄ Si: C, 60.64; H, 5.09. Found: C, 60.36;H, 5.16.

NMR (CDCl₃): -0.04 (9,s), 2.95 (2,s), 3.46 (1,d, 18.0 Hz), 3.70 (1,d,18.0 Hz), 3.84 (3,s), 4.83 (2,s), 6.80 (1,s), 7.30 (5,m).

(b) Ethyl[6,7-dichloro-1-oxo-2-(p-chlorophenyl)-2-(3-trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.Reaction of ethyl[6,7-dichloro-1-oxo-2-(p-chlorophenyl)-5-indanyloxy]acetate with1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure ofExample 1, STEP (b), affords the title compound, m.p. 103°-103.5°;purified by chromatography (silica-gel column eluted withchloroform-n-hexane) and crystallization from ether-cyclohexane.

Anal. Calcd. for C₂₅ H₂₅ Cl₃ O₄ Si: C, 57.32; H, 4.81; Cl, 20.31. Found:C, 57.24; H, 4.85; Cl, 20.47.

NMR (DMSO-d₆): -0.10 (9,s), 1.24 (3,5, 7.2 Hz), 2.94 (2,s), 3.47 (2,s),4.20 (2,q, 7.2 Hz), 5.10 (2,s), 7.31 (5,m).

(c) Ethyl[6,7-dichloro-1-oxo-2-(p-fluorophenyl)-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.Reaction of ethyl[6,7-dichloro-1-oxo-2-(p-fluorophenyl)-5-indanyloxy]acetate with1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure ofExample 1, STEP (b), affords the title compound as an oil.

NMR (CDCl₃): -0.10 (9,s), 1.22 (3,t, 7 Hz), 2.78 (2,s), 3.45 (2,m), 4.20(2,q, 7 Hz), 4.72 (2,s), 6.73 (1,s), 7.2 (4,m).

(d) Ethyl[6,7-dibromo-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.Reaction of ethyl (6,7-dibromo-1-oxo-2-phenyl-5-indanyloxy)acetate with1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure ofExample 1, STEP (b), affords the title compound.

(e) Ethyl[6,7-dichloro-1-oxo-2-phenyl-2-(4-(trimethylsilyl)-3-butyne)-5-indanyloxy]acetate.Reaction of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate with1-bromo-4-(trimethylsilyl)-3-butyne according to the procedure ofExample 1, STEP (b), affords the title compound.

EXAMPLE 4[6,7-Dichloro-1-oxo-2-(p-chlorophenyl)-2-propargyl-5-indanyloxy]aceticAcid

Desilylation and hydrolysis of ethyl[6,7-dichloro-1-oxo-2-(p-chlorophenyl)-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetatewith sodium hydroxide in ethanol according to the procedure of Example1, STEP (c), affords the title compound, m.p. 200°-201°.

Anal. Calcd. for C₂₀ H₁₃ Cl₃ O₄ : C, 56.70; H, 3.10; Cl, 25.11. Found:C, 56.37; H, 3.27; Cl, 25.16.

NMR (DMSO-d₆): 2.75 (1,t, 2.1 Hz), 2.96 (2,d, 2.1 Hz), 3.54 (2,s), 5.02(2,s), 7.34 (5,m).

EXAMPLE 5 [6,7-Dichloro-1-oxo-2-(p-fluorophenyl)-5-indanyloxy]aceticAcid

Desilylation and hydrolysis of ethyl[6,7-dichloro-1-oxo-2-(p-fluorophenyl)-2-(3-trimethylsilyl)-2-propynyl)-5-indanyloxy]acetatewith sodium hydroxide in ethanol according to the procedure of Example1, STEP (c), affords the title compound, m.p. 189°-190°.

Anal. Calcd. for C₂₀ H₁₃ Cl₂ FO₄ : C, 58.99; H, 3.22; Cl, 17.42. Found:C, 59.82; H, 3.23; Cl, 17.69.

NMR (DMSO-d₆); 2.75 (1,t, 2.0 Hz), 2.95 (2,d, 2.0 Hz), 3.55 (2,s), 5.02(2,s), 7.24 (5,m).

EXAMPLE 6[6,7-Dichloro-1-oxo-2-phenyl-2-(3-butynyl)-5-indanyloxy]-acetic Acid

Desilylation and hydrolysis of ethyl[6,7-dichloro-1-oxo-2-phenyl-2-(4-(trimethylsilyl)-3-butyne)-5-indanyloxy]acetatewith sodium hydroxide in ethanol according to the procedure of Example1, STEP (c), affords the title compound.

EXAMPLE 7 (6,7-Dibromo-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)aceticAcid

Desilylation and hydrolysis of ethyl[6,7-dibromo-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetatewith sodium hydroxide in ethanol according to the procedure of Example1, STEP (c), affords the title comound.

EXAMPLE 8 Preparation of 5-Hydroxyindanones of Formula II

(a) 2,3-Dichloro-5-phenylacetylanisole.

Aluminum chloride (23.55 g., 176.6 mmol) is added portionwise to astirred solution of 2,3-dichloroanisole (31.02 g., 175.2 mmol),phenylacetyl chloride (27.01 g., 174.7 mmol), and carbon disulfide (25ml.) with cooling at 0° over a 20 min. period. After standing at ambienttemperature for 16 hrs., the carbon disulfide solvent is removed underreduced pressure. Residual material is slowly treated with a mixture of50 ml. of concentrated hydrochloric acid and about 300 ml. of awater-ice mixture to give a light yellow solid which is taken up inmethylene chloride. The methylene chloride solution washed with water,dried over magnesium sulfate, and concentrated under reduced pressureaffords 84.7 g. of crude material which purified by crystallization frombenzene-cyclohexane provides 38.7 g. (75% yield) of2,3-dichloro-5-phenylacetylanisole, m.p. 127°-129.5°.

(b) 2,3-Dichloro-4-(2-phenylacryloyl)anisole.

Acetic anhydride (150 ml.) is added dropwise to a suspension of2,3-dichloro-4-phenylacetylanisole (8.95 g., 30.3 mmol) in 15.3 ml. ofN,N,N',N'-tetramethylenediaminomethane under an atmosphere of argon withice-bath cooling. The reaction mixture stirred at 25° for 2 hrs. andpoured into ice-water affords 11.9 g. of beige solid. An etherealsolution of the solid is washed with hydrochloric acid, water and thendried over magnesium sulfate. Removal of the solvent under reducedpressure provides 8.77 g. (94% yield) of2,3-dichloro-4-(2-phenylacryloyl)anisole, m.p. 83.5°-86°.

(c) 2-Phenyl-5-methoxy-6,7-dichloro-1-indanone.2,3-Dichloro-4-(2-phenylacryloyl)anisole (8.2 g., 26.8 mmol) in 215 ml.of methylene chloride is added dropwise over a 4.5 hr. period to astirred solution of 107 ml. of sulfuric acid in 107 ml. of methylenechloride at 0°-5° under an atmosphere of argon. Following addition, thereaction mixture is stirred for 0.5 hr., poured over about 300 g. ofcrushed ice and the aqueous-organic phases separated. The aqueous phaseis extracted with methylene chloride and the combined methylene chloridesolutions sequentially washed with water and then dried over magnesiumsulfate. Removal of the solvent affords 8.52 g. of solid whichcrystallized from benzene-cyclohexane provides 4.59 g. (56% yield) of2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 193.5°-196.5°.

(d) 2-Phenyl-5-hydroxy-6,7-dichloro-1-indanone.

A stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (5.18g., 16.8 mmol) and pyridine hydrochloride (23.3 g., 202 mmol) is heatedat 190° for a period of 2 hrs. and then poured into 300 ml. of cold 2 Nhydrochloric acid. Insolubles are collected, dried and crystallized fromethanol to afford 3.7 g. (75% yield) of2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 252°-253.5°.

Following the above procedure of Example 8 (a-d) but employing anequimolar amount of the aralkyanoyl halides listed below:

p-chlorophenylacetylchloride,

p-fluorophenylacetylchloride,

in place of phenylacetylchloride, there is produced, respectively,

(1) 2-(p-chlorophenyl)-5-hydroxy-6,7-dichloro-1-indanone, m.p.278°-280°.

Anal. Calcd. for C₁₅ H₉ Cl₃ O₂ : C, 55.00; H, 2.77; Cl, 32.47. Found: C,54.77; H, 2.81; Cl, 32.24.

(2) 2-(p-fluorophenyl)-5-hydroxy-6,7-dichloro-1-indanone, m.p.275°-276°.

Anal. Calcd. for C₁₅ H₉ Cl₂ FO₂ : C, 57.91; H, 2.92; Cl, 22.79. Found:C, 58.05; H, 2.71; Cl, 23.15.

Following the above procedure of Example 8 (a-d) employing2,3-dibromoanisole for 2,3-dichloroanisole affords

(3) 2-phenyl-5-hydroxy-6,7-dibromo-b 1-indanone.

What is claimed is:
 1. A silylated compound of Formula IV ##STR13##wherein n is 1 or 2;X is halo; R₁ is phenyl or p-halophenyl; and R₃ islower alkyl.
 2. The compound of claim 1 in which X is chloro.
 3. Thecompound of claim 1 in which n is 1 and X is chloro.
 4. The compound ofclaim 1 which is methyl[6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.5. The compound of claim 1 which is ethyl[6,7-dichloro-1-oxo-2-phenyl-2-(3-trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.6. The compound of claim 1 which is ethyl[6,7-dichloro-1-oxo-2-(p-chlorophenyl)-2-(3-trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.7. The compound of claim 1 which is ethyl[6,7-dichloro-1-oxo-2-(p-fluorophenyl)-2-(3-trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate.